B1 TOXICOLOGY AND EPIDEMIOLOGY

Question 1

WHAT DOES LABELLING AND PACKAGING OF SUBSTANCES AND MIXTURES (CLP). REQUIRE MANUFACTORERS AND SUPPLIERS TO DO?

Answer 1

CLP implements the GHS within Europe law.

CLP requires manufacturers and suppliers to:

• Classify dangerous chemicals (using new GHS criteria).
• Notify the European Chemicals Agency (ECHA) of CLP classification.
• Label (using new GHS pictograms and statements).
• Package chemicals safely.

Question 2

What are the aims of CLP?

Answer 2

AIMS OF CLP

Impose a duty on the manufacturers and suppliers of chemicals to:

Classify those chemicals according to their:

• physicochemical properties (e.g. explosive).
• health effects (e.g. irritant); and
• environmental effects (e.g. toxic to fish).
• Label the chemical appropriately.
• Package the chemical safely.

Question 3

Define inhalable dust (or total inhalable dust):

Answer 3

“the fraction of airborne dust that enters the nose and mouth during breathing, and is therefore available for deposition in the respiratory tract”.

Question 4

Define respirable dust?

Answer 4

“the fraction of airborne dust that penetrates to the gas exchange region of the lung”.

Typically, only dust particles of less than 7μm in diameter will reach the deep lung.

NB: 1μm = 1/1000 mm (1 x 10-3 mm)

Question 5

Define thoracic dust?

Answer 5

The fraction of airborne dust that deposits in the conducting airways (trachea, bronchi and bronchioles) but does not penetrate to the terminal bronchioles or alveoli.

Question 6

What are epidemiological studies?

Answer 6

Investigation of populations over a significant period of time – see how outcome of exposure unfolds over time.

Question 7

What is a case-control study?

Answer 7

Compares people who already have a specific disease with those who do not (i.e. outcome selective).

retrospective (outcome known – looking back at events).

Question 8

What is a cohort study?

Answer 8

Compares those exposed to suspected causes with those who are not (i.e. exposure selective).
May be retrospective or prospective (follow-up).

Question 9

How does the case control study operate?

Answer 9

Comparison of CASE and CONTROL groups:

“CASE” – group who have disease/condition of interest.

“CONTROL” – group similar to case group except don’t have the disease.

Look at: exposure history, employment history, medical records, etc. to establish differences which might imply association between disease incidence and particular risk factors.

Question 10

how does the prospective cohort study work?

Answer 10

Population selected for exposure characteristics (both initially free of the disease) and followed for period of time - then outcome (disease) measured.

Try to establish association between exposure and effect (e.g. exposure to asbestos and incidence of lung cancer).

Uses two groups (“cohorts”):
Exposed.
Unexposed (the control group).

Incidence of specific disease calculated for each group and statistically analysed.
If significantly more people develop the disease in exposed group – strongly suggestive of causal connection (though not absolute proof).

Question 11

What is retrospective cohort study?

Answer 11

Population selected based on past exposure records, i.e. a historic cohort is assembled.

The current outcomes of that exposure are investigated for both exposed and unexposed cohorts.
Much quicker than prospective cohort study (“follow-up” period has already occurred in the past!)

Question 12

What is toxicology?

Answer 12

The study of the adverse effects of chemicals on living organisms and the symptoms, mechanisms, detection and treatment of those effects.

Question 13

advantages of animal testing?

Answer 13

Does not rely on exposing people to chemicals (no human disease/suffering involved).

Can be quicker/cheaper than epidemiology on humans.

Provides information that would otherwise be difficult to get.

Allows the long-term effects of exposure to low doses to be studied (chronic tests).

Question 14

limitations of animal testing?

Answer 14

Variations between species – application of results to humans may be questionable.
Ethical issues.

Contributing factors (e.g. smoking, diet) will not be apparent in animal studies.

Lengthy and expensive.

Question 15

alternatives to animal testing?

Answer 15

In-vitro studies:
E.g. Ames mutagenicity test.

Predictive studies:
Grouping and read-across.
Quantitative Structure Activity Relationship (QSAR) studies.

Question 16

IN VITRO TEST:TESTING FOR MUTAGENIC POTENTIAL: THE AMES TEST FOR GENETIC MUTATION

Answer 16

Quick, cheap and easy – often as preliminary study to detailed animal study.

Uses bacteria (e.g. salmonella) genetically modified so needs histidine (an amino acid) to be able to multiply (normal strains of bacterium don’t need histidine).

Test bacteria initially incubated in histidine-deficient medium (so no growth takes place).

If mutagen added – causes genetic changes which reverse original genetic modification - bacteria can now grow/multiply.
i.e. GROWTH = Reverse Mutation =

Substance is mutagenic (and carcinogenic).

Can get false positive/negative results!

Question 17

Give information on predictive studies?

Answer 17

Grouping and read-across - predicts the possible toxic properties of a substance by reference to chemically-related substances whose toxic properties are well understood.

Quantitative Structure-Activity Relationships (QSAR) - models the structure of the chemical and attempts to predict molecular shape, bonds, activity and how the chemical will interact with human biochemistry.

These methods can indicate need for further actual testing.
Usually rapid, relatively cheap but dependent on data quality

Question 18

What is the dose/response relationship?

Answer 18

DOSE - amount of substance per unit body mass to which the organism is exposed.
RESPONSE - the resultant effect, e.g. death.

Question 19

What does Response depend on?

Answer 19

Dose.

Duration over which dose given.

Route of administration.

Species, e.g. rats vs humans.

No simple dose-response relationship for carcinogens, mutagens and reproductive toxins! (as discussed earlier).

Question 20

What is LD50?

Answer 20

LD50 relates to a single oral dose that is ingested and kills 50 per cent of a test population. Since it is an oral dose, LD50 is measured in terms of milligrams (or
grams) per kilogram body weight.

Question 21

What is LC50?

Answer 21

LC50, on the other hand, is an inhaled concentration sufficient to kill 50 per cent of a test population in a fixed period of time and is
measured in milligrams (or grams) per cubic metre of air.

Question 22

Explain the meaning of the term ‘carcinogen’.

Answer 22

A ‘carcinogen’ is an agent that causes cancer; has the ability to produce malignant
tumours, attacks cell reproduction mechanisms;

causes changes in cell’s DNA resulting in abnormal cells and uncontrollable growth;

and

produces effects that are irreversible and continue well after the initial exposure.

Question 23

Describe the physiological effects of carbon monoxide on the body

Answer 23

the physiological effects of carbon monoxide on the body and the symptoms that might be
experienced by persons exposed to the gas.

carbon monoxide being absorbed via the lungs into the bloodstream and displacing the
oxygen by chemically bonding to haemoglobin, hence reducing the oxygen carrying capacity of the blood and reducing the supply of oxygen to tissues.

Carbon monoxide is only slowly displaced from the body and its symptoms should have included reference to drowsiness, headaches, dizziness, breathlessness, unconsciousness
and, ultimately, death.

Question 24

Outline the control measures that could be used to reduce exposure to carbon monoxide in a motor vehicle repair premises.

Answer 24

minimising the duration of engine running time,

providing local exhaust ventilation
attached to the vehicle exhaust pipe,

providing a good standard of general ventilation for the workshop and inspection pits,

carrying out regular maintenance of the
ventilation systems,

using a carbon monoxide monitor or alarm,

providing specific information,

instruction and training for the employees and isolating or segregating the area from customers.

Question 25

Describe the ways the body may defend itself against inhaled dusts.

Answer 25

the body’s first line of defence is the nasal hairs which trap and filter out dust particles greater than ten microns in size.

Mucus in the nose and mouth also traps these particles which are subsequently ejected by sneezing, blowing the nose and spitting.

Dust particles between five and ten microns tend to settle in the mucus covering the bronchi and broncioles and are wafted upwards by tiny hairs – the ciliary escalator – towards the throat.

They are then coughed and spat out. Particles smaller than five microns are more likely to reach the lung tissue.

These particles are ingested by macrophages – a type of white blood cell – in a process known as phagocytosis and transported back to the ciliary escalator or to the lymphatic system. They may also be transported across
the alveolar membrane into the blood stream.

Question 26

A company uses a substance in the form of a powder, which is added directly to a mixing vessel from sacks, during the
manufacture of paints.

Outline the practical control measures that could be used to minimise exposure during the addition. (8)

Answer 26

elimination of the coloured powder was not an option since the colour range was required.

Consequently they were expected to outline
practical control measures such as introducing the colouring agent in a pellet or dye solution form.

If this was not possible, then the powder could be fed into the mixing vessel by means of an automated hopper feed system and screw conveyor with the powder being emptied into the hopper through an opening provided with local exhaust ventilation.

A vacuum cleaner should be used to clear up spillages and employees should be provided with personal protective equipment such as overalls, gloves and goggles.

Some form of respiratory protection would also have to be provided.

If the dust was thought to be nuisance only, then a particle filtering face piece – a disposable face mask – changed on a regular basis could suffice.

However, a filter respirator would have to be worn if the powder were found to be harmful.

Question 27

Compare and contrast the following epidemiological methods: Retrospective Cohort Study and Prospective Cohort Study.

Answer 27

a retrospective cohort study starts at a point in the past and follows cohort forward in order to
determine past exposure histories and health outcomes from records;

a prospective cohort study starts at the present time and follows cohort forward and enables monitoring of exposure and health outcomes.

Question 28

Outline factors that may affect the reliability of these epidemiological
methods.

Answer 28

the cohort size;

the accuracy of historical data on exposure and health effects;

the accuracy of diagnosis;

there may be non-occupational exposure;

long latency periods for the effect;

the frequency of disease in unexposed cohort;

lifestyle factors such as alcohol consumption, diet, smoking etc;

there may be selection bias (cohort may not be representative of exposed population);

the ‘healthy worker effect’ (sick people leave);

and

the difficulty in following all of cohort for
instance a geographic move, non co-operation etc.

Question 29

Outline the structure of the skin.

Answer 29

The skin is made up of three layers the epidermis, consisting of dead cells that are
continually shed and provide protection for the inner layer, the dermis comprising living
cells and containing blood capillaries, nerve endings, and sweat sebaceous glands;
and the subcutaneous layer containing arteries, veins and fat.

Question 30

Outline how hazardous substances can enter the body through

the skin.

Answer 30

the skin is partially permeable
and substances that are soluble in water or fat may migrate or be absorbed through
the skin and enter the blood stream and have a systemic effect.

Hazardous substances may also enter via cuts or abrasions while corrosive substances can burn through the layers of skin and enter the blood stream.

There is also the possibility that
substances can enter the body by injection such as in the use of needles.

Question 31

Construction company employees regularly lay floors and use a cement-based levelling compound which contains chromium VI.

Several of the long term employees and one of the new recruits have complained about red and sore skin on their hands.

Explain the possible reasons for the symptoms they are
now experiencing.

the symptoms suggest that the
employees have contracted dermatitis since cement is a well-known irritant that may
cause this disease.

The longer term employees may be suffering from irritant contact dermatitis caused by chronic or repeated exposure to an irritant which ultimately de-fats and de-greases the skin and overcomes the skin’s own defence and repair systems.

Answer 31

The symptoms may also be caused by allergic contact dermatitis following contact with a sensitiser, for example, the chromium compound impurities within the
cement which produces an over-reaction from the body’s immune system.

Sensitisation can occur following the first contact as with the new recruit or after some
time as with the longer term employees. Further reasons for the symptoms include
caustic burns and friction from the general floor laying process.

Question 32

Outline control measures that could be used to minimise these symptoms in this situation.

Answer 32

the use of a non-cement levelling compound such as a polymeric product;

minimising contact with the material by the use of hand tools and wearing gloves;

washing contaminants from the skin as soon as possible and drying the skin thoroughly after washing;

using pre and after work moisturising creams
to replenish oils;

informing the employees of the hazards associated with the operation and the precautions to be taken;

and encouraging them to report any skin problems;

and

arranging for supervisors to carry out regular skin inspections of the workforce.

Question 33

Human epidemiology and animal studies are methods that can be used to investigate whether a substance is carcinogenic.

Outline the advantages of EACH of these methods.

Answer 33

human epidemiology is a definitive method for identifying human carcinogens, is based on
experience in actual populations and can be done retrospectively.

The advantages of using animal studies on the other hand include the fact that this method avoids human exposure and hence possible human risk;

the data can be collected more quickly than
by using epidemiological methods; the animal study environment can be better
controlled;

and

animals provide the best available models as, biochemically, they relate more closely to human

Question 34

Human epidemiology and animal studies are methods that can be used to investigate whether a substance is carcinogenic.

Outline the disadvantages of EACH of these methods. (7)

Answer 34

one of the disadvantages of using human epidemiology, apart from its cost and the amount of time it takes, is that it usually requires large populations in order to reduce random sampling errors that may otherwise distort the real underlying picture;

it suffers from problems of sensitivity – how well it can detect those either with
the disease or the effect of the substance being tested – and conversely specificity –
how well it can detect those without the disease or the effect.

Additionally, human epidemiology may rely on poor or inaccurate historical records;

the study may be affected by lifestyle factors;

it is not very useful for assessing completely new substances since latency periods may be extensive

and

finally the study might be affected by potentiation together with synergistic, additive or antagonistic effects.

The disadvantages of animal studies include the fact that that the dose/response
effect may vary in different animal species and so extrapolating data to humans may
not always be reliable.

Additionally, conducting animal studies can be time-consuming and expensive dependent on the species used and there are often ethical
considerations and public opinion that can make this approach more difficult to
undertake.

Question 35

Review the merits and limitations of each of the following methods for Identifying the carcinogenic
potential of a substance.

Human epidemiology

Answer 35

MERITS

• involves the application of established
methodologies

• techniques are validated, statistically-based & directly applicable to human exposures

• identify patterns of ill-health and potential
causal relationships

LIMITATIONS

• Requires large populations / cohorts for analysis
- need to track cohorts over long periods

• Resource intensive / time-consuming (delayed results) and requires high levels of expertise

• Results can be inconclusive - difficulty in
screening out confounding factors - social /
environmental / lifestyle / age / gender etc

• Reliability of data is questionable (medical
records, death certificates, recall etc)

Question 36

Review the merits and limitations of each of the following methods for Identifying the carcinogenic
potential of a substance.

Animal studies

Answer 36

MERITS

• Avoids human exposures

• Results produced more quickly than above

• Certain species provide a good analogy for
human exposures

• No complications of tracking cohort etc

LIMITATIONS

• Results may not reflect human response to
similar exposures (2-napthylamine = bladder
cancer in humans not in rats)

• Animal studies tend to focus on acute effects - human cancers often involve chronic effects
• Animal studies are “artificial” and do not reflect the complexity of human exposures - diet / smoking etc
• Ethical objections to animal testing

Question 37

Review the merits and limitations of each of the following methods for Identifying the carcinogenic

In vitro mutagenicity testing

Answer 37

MERITS

• Ames test = widely used / validated / recognised methodology
• Quick and inexpensive
• No ethical issues
• Can form preliminary basis for further in vivo testing

• Can help identify mutagenic / carcinogenic
mechanisms

LIMITATIONS

• Results not always relevant to human exposures

• Not all mutagens are carcinogens(= false
positives)

• Results from Ames test may be unreliable - false positives / false negatives

Question 38

COSHH assessment is a five-step process: what are these steps?

Answer 38

1. Gather information about the substances, the work and the working practices.
2. Evaluate the risks to health.
3. Decide on the control measures needed to comply with COSHH.
4. Record the assessment.
5. Review and update as necessary.

Question 39

Factors to Consider in the Assessment of Risks to Health From Chemicals

Answer 39

Hazardous properties of the substance.

Type and level of exposure.

Duration and frequency of exposure.

Numbers of people.

Effect of mixtures.

Unusual activities.

Workplace Exposure Limits (WELs).

Existing controls.

Surveillance and monitoring results.

Individual susceptibilities.

Question 40

A number of employees working in a busy city centre hair salon have reported problems of skin irritation on their hands, which for at least one employee has been diagnosed as contact dermatitis.

Advise the salon manager on the likely causes and the steps that could be taken to overcome these instances of contact dermatitis.

Answer 40

Likely causes of contact dermatitis in this context include:

repeated and prolonged contact with hot
/ cold water, soap, detergents, bleaches, dyes, irritant materials, hot air;

abrasion of the skin during washing, drying and styling

Other contributory factors can include the person’s individual susceptibility (in some cases the presence of pre-existing medical conditions or immuno-suppression);

poor hygiene - not cleaning dyes
etc off hands;

not using PPE - gloves

Steps that could be taken in relation to contact dermatitis include:

introducing a proactive skin care
regime / policy;

pre-employment screening to identify susceptible / atopic individuals;

ensuring SDS available for all hazardous materials - dyes etc;

eliminating hazardous materials / allergenic products;

substitution;

job rotation - avoid prolonged exposures / wet work etc;

hygiene facilities;

barrier creams;

PPE;

training and information on hazards / precautions / early signs;

regular health surveillance - self
inspection / questionnaire / appointed person

Question 41

What does REGISTRATION, EVALUATION, AUTHORISATION AND RESTRICTION OF CHEMICALS (REACH) require manufacturers and suppliers to do?

Answer 41

Requires (amongst many other things) manufacturers and suppliers to:

• Register chemicals that they manufacture or supply (>1 tonne p.a.) with the European Chemicals Agency (ECHA).
• Submit dossier of information on those chemicals (may require further testing to fill data gaps).
• Provide a safety data sheet (SDS) to customers.

ECHA then evaluates portfolios of chemical data:

• For substances of very high concern (SVHCs) manufacturers/ suppliers may be required to gain authorisation prior to use.
• Very high risk substances may be restricted.